Fibrosis occurs when excess fibrous connective tissue forms or develops in an organ or tissue. Fibrosis can occur as a part of the wound-healing process following tissue damage resulting from physical injury, inflammation, infection, exposure to toxins, and other causes. Examples of conditions associated with tissue fibrosis include dermal scar formation, keloids, liver fibrosis, kidney fibrosis (including diabetic nephropathy), hepatic cirrhosis, pulmonary interstitial fibrosis, glomerulonephritis, heart failure (ischaemic and non-ischaemic), diabetic nephropathy, scleroderma, excessive scar tissue post surgery or device insertion, progressive kidney disease, hypertension, heart failure due to ischaemic heart disease, valvular heart disease, hypertensive heart disease, and hypertrophic scars.
The elaboration of extracellular matrix also has a role in fibroproliferative tumor progression and metastasis. Accordingly, strategies that reduce the accumulation of extracellular matrix have been advocated as potential therapies for the treatment and prevention of heart failure in both diabetic and nondiabetic states.
At present the pathogenic mechanism of fibrosis is not completely understood. In general, the proliferation and function of fibroblasts are closely controlled in normal conditions. However, in pathological states in which inflammation or tissue injury is serious or sustained, the tissue repair mechanism goes into overdrive and the control mechanism is abrogated. Excessive tissue repair is caused by over-production of connective tissue protein probably due to abnormal proliferation of fibroblasts and extracellular matrix dysbolism. The cytokines causing such a phenomenon include, fibroblast growth factor (FGF family), transforming growth factor (TGF-β), platelet derived growth factor (PDGF), etc.
Anti-inflammatory agents have been used to treat fibrosis with the aim of suppressing chronic inflammation, but such treatments can be unsatisfactory in terms of efficacy and side effects. Numerous studies have been performed to obtain substances that inhibit the production or the activity of the cytokines thought to be involved in fibrosis. Tranilast (n-[3,4-dimethoxycinnamoyl]anthranilic acid) is an anti-fibrotic agent used in Japan for the treatment of fibrotic skin disorders such as keloids and scleroderma. Although the precise mechanisms and mode of action of tranilast are incompletely understood, its ability to inhibit ERK phosphorylation, a major intermediate in the TGF-β signalling pathway, may underlie its antifibrotic effects, with known actions of tranilast including the inhibition of TGF-β-induced extracellular matrix production in a range of cell types. Tranilast has also been shown to attenuate TGF-β-induced collagen synthesis in cardiac fibroblasts using an experimental model of diabetic cardiac disease, and to reduce inflammation in allergic diseases, such as allergic rhinitis and bronchial asthma, etc. In addition, tranilast has been shown to have anti-proliferative activity.
However, it has recently been shown that genetic factors in certain patients may confer susceptibility to tranilast-induced hyperbilirubinemia. One possibility for how this may arise is the presence of Gilbert's syndrome polymorphisms of the glucuronosyltransferase UGT1A1, which leads to increased susceptibility to tranilast-induced hyperbilirubinemia. Such hyperbilirubinemia may result from the low level of UGT1A1 glucuronosyltransferase present in individuals with this syndrome. Tranilast itself, and its major metabolite N3 (4-desmethyl-tranilast), have been shown to be inhibitors of UGT1A1, potentially leading to aberrant metabolism of bilirubin and its accumulation.
Accordingly, compounds that are based on tranilast have the potential to provide further biologically active compounds that would be expected to have useful, improved pharmaceutical properties with potential anti-fibrotic, anti-inflammatory, and anti-proliferative or anti-neoplastic activity for the treatment or prevention of diseases associated with fibrosis, diseases characterised by inflammation or neoplastic disease (both benign and malignant), and as alternatives/adjuncts to tranilast.